New nitrofuranacrylic derivatives



United States Patent NEW NITROFURANACRYLIC DERIVATIVES Haruo Saikachi, Oaza Kanehira, Fukuoka-shit, Japan, assignor to Masajiro Ueno, Nishinomiya, Japan No Drawing. Filed Sept. 4, 1959, Ser. No. 838,033 Ciaims priority, application Japan Mar. 18, 1959 Claims. (Cl. 260-240) The present invention relates to new nitrofuran deriva tives and more particularly to substituted 5-nitro-2-furyl acrylic acid or its acid amide having an improved antibacterial activity and represented by the following chemical formula:

OzNl J-OH=C-C 0 R: O l

wherein R represents phenyl radical or furyl radical and R stands for hydroxy radical or amide radical.

'I have found that the present new nitrofuran derivatives resulting from substitution of hydrogen atom at aposition in' side chainof nitrofuryl acrylic acid or its amide with phenyl or furyl radical has a considerably higher antibacterial activity and lower toxicity than those of the hitherto known nitrofuran derivatives. The nitrofuran derivatives of the present invention are acknowledged to be advantageously employed as chemotherapeutic preparation for various bacterial diseases. For example, bacterial intestinal disorders, such as dysentery and the like, and also bacterial disease may be expected to be eifectively treated with a minor amount of any one of the new nitrofuran derivatives of this invention. In case the known nitrofuran derivatives are used as an antiseptic or as a therapeutic agent for coccidium of chicken or an ingredient of ointment, said derivatives would give only a remarkably lower antibacterial activity than the activity in vitro. However, the new nitrofuran derivatives of this inventionhardly show the lowering of the activity.

The nitrofuran derivatives of the presentinvention can be used, for example as antiseptics, therapeutics and the like, as it is or in a form of mixture of them or a mixture with any other antiseptics for the purpose of removing the bacterial derangements of living creatures; For instance these new derivatives exhibit a considerably improved antiseptic activity by a simple operation for example such as addition of them as they are to the foods or dipping of the food in a solution of the new derivatives. For therapeutics, these derivatives also have a wonderful efiect for the bacterial disorder in a conventional form such as ointment, power and thelike.

The new nitrofuran derivatives of this invention may be synthesized by a new process. For example, nitrofuryl-u-phenyl (or furyl) acrylic acid can be synthesized by Parkin reaction from nitrofurfural and alkali metal salt of phenyl (or furyl) acetic acid. From this nitrofuryl-u-phenyl (or furyl) acrylic acid, acid amide thereof can be obtained in. a good yield.-

I have found from my experiments that new nitrofuran derivatives of this invention cannot be synthesized by such a process as to first produce S-nitro-Z-furyl acrylic 3,031,447 Patented Apr. 24, 1962 acid and then substitute hydrogen atom at d-POSitlOD. of said acrylic acid with phenyl or furyl radical. It is clear, therefore, that the present compounds are not derivatives from 5-nitro-2-furyl acrylic acid.

This invention will be fully explained by way of practical examples for producing the new nitrofuran derivatives and the preparations consisting of or containing them.

SYNTHESIS OF-S-NITRO-Z-FURYL-a-PHENYL ACRYL AMIDE A mixture of 30 gms. of S-nitrofurfural, 38 gms. of potassium phenyl acetate and 430 gms. of acetic anhydride is stirred at about 37 C. for about 10 hrs., after which a large amount of water is added to the reaction mixture under continuation of reaction to decompose acetic anhydride. On ice-cooling of the reaction solution yellowish brown crystals may be obtained. Said crystals are recrystallized from 200 cc. of benzene, whereupon 20 gms. of light yellow crystals, M.P. 159 C., can be obtained. This crystal is S-nitro-Z-furyl-a-phenyl acrylic acid.

PREPARATION OF S-NlTRO-Z-FURYL-a-PHENYL ACRYL AMIDE A mixture of 12 gms. of 5-nitro-2-furyl-a-phenyl acrylic acid crystal and 30 gms. of thionyl chloride is heated in a vessel provided with a reflux condenser and calcium chloride tube at 70 C. for about 10 hrs. After completion of the reaction thionyl chloride is distilled off under reduced pressure (30 mm. Hg) to give a dark brown residue, from which 12 gms. of light yellow crystals, M.P. C., are obtained by twice recrystallizations with benzene. 7 gms. of said crystal is dissolved in 60 cc. of benzene followed by introducing ammonia gas to the solution, thereby light yellow crystals, M.P. 169 C., are precipitated. Recrystallization of said crystals from 70 cc. of methanol gives 5 gms. of crystal 5-nitro-2-furyl-aphenyl acryl amide, M.P. 170 C.

SYNTHESIS OF S-NITRO-Z-FURYL-oc-FURYL ACRYL AMIDE 4.3 gms. of S-nitrofurfural is added to a mixture of 5 gms. of potassium furyl acetate and 50 gms. of acetic anhydride with stirring at 60 C. for 6 hrs. After completion of the reaction, the reaction mixture is poured into water and heated at 60 C. for 0.5 hr. to decompose acetic anhydride which leads to formation of dark red crystals. Recrystallization of said crystal from methanol gives 6 gms. of crystal 5-nitro-2-furyl-a-furyl acrylic acid, M.P. 178 C. By the same treatment of said crystals as in the preceding example S-nitro-Z-furyl-a-furyl acryl' amide may be obtained.

Acid amides of this invention may also be prepared from furfural itself by a process which comprises at first binding to furfural a-phenylor a-furylacrylic acid as side chain, nitrating at 5-position of furan nucleus to form nitrofuryl-a-phenyl (or furyl) acrylic acid and converting it to acid amide thereof. 7

Characteristics and antibacterial activity of the nitrofuran derivatives of this invention will be shown in the following Tables I and Table I M.P., Maximum Compound Formula 0. absorption Remarks Wave length 5-nitro-2-fury1-a-phenyl acrylic acid fl L 0 OH 160-161 Light yellow crystal.

-nitro-2-furyl-a-pheny1 acryl am1de i J 170 2,800,'3,600A. Do.

e-nitro-z-furyl-a-furyl acrylic acid N aL H O0H 178 Red crystal,

5-nitro-2-furyl-cr-furyl acryl amide NO; H C-O ONE: 151 2,200, 3,050A Orange crystal.

Table 11 The nitrofuran derivatives of the present invention have considerably high therapeutic efi'ect for various bacterial diseases as shown in the following clinical demonstrations using 5-nitro-2-furyl-a-furyl acryl amide.

St E M. (A) DIRECTIONS AND DOSAGE Formula. subtilis aureus cereus flcwus 40 Bacteria 0.10.2 gram were given 3-6 time a, day to cases of Concentration for inhibition of acute and chrome dlarrhoea' wt 'rl B. CURATIVE VALUE times a day was completely cured by administration for cn=0-oo0n 10 5 50 4 days of 0.18 gram a day.

(1) A case who has loose bowels from fifteen to twenty OzNl fl- (2) A case of acute diarrhoea was completely cured by administration for 2 days of 0.18 gram a day.

(3) A case of chronic diarrhoea Whose excretion being mixed with mucus, blood and pus Was completely cured on the fourteenth day by administration of 0.18 gram a day. i (4) A case of intestinal tuberculosis who evacuate 0,N 011:0-0 ONE: 25 1 50 Watery excretion was completely cured by administration for 7 days of 5-6 times of 0.18 gram a day.

(5) Whole of the demonstrations mentioned above were not shown any ill effects.

The therapeutic effect mentioned above has been acknowledged with other nitrofuran derivatives of this invention.

The nitrofuran derivatives of this invention can be com- OgN O/CH=CO0OH 25 50 5 50 pounded with any other ingredients which are commonly used for tablet.

0 This nitrofuran of this invention can be simply incorpoa rated into ointment basis to give an ointment having antibacterial activity. For ointment basis, conventional petroleum products, wax and the like may be employed. 02N o --OH=O-CONH2 2.5 10 0. 5 2 One example will be illustrated as follows:

PREPARATION OF OINTMENT HAVING ANTIBACTERIAL ACTIVITY NOTn.Cu1ture medium: 0.5% peptone, 0.5% glucose, 1 of finely Pulvelized y -P cnyl acryl g gzi eggt t c ts. pH 7-0, stcrllize a 115 Pounds P amide, particle size of which is 0.5-3p. is mixed with and Cultivation: at 37 c. fo1'48 hours. Suspended in 6.5 of q d parafine by the treatment for 150 hrs. on ball-mill. Aforesaid suspension containing nitrofuran is added to the mixture of 942.5 kg, of white Vaseline and 50 kg. of white wax, which mixture having been heated at 85 C. and then cooled to 60 C., and cooled to 45-48 C. to solidify. Now 84.5 gms. of water is added to a mixture of 10 gms. of the ointment thus obtained, 5 gms. of sorbitanmonostearate and 0.5 gm. of sodium carboxy methyl cellulose and emulsified by blender under heating to about 70 C. The comparison of inhibition rings tested according'to the standard cup method on B. subtilis as control is as follows:

Nitrofuran Control ointment, mm.

I have also discovered that a poultry-feed incorporated with the new nitrofuran derivatives can control the disorder of the poultry by microorganisms. The new nitrofur-an derivatives may be merely incorporated into the poultry-feed without taking their composition into account. Anticoccidium feed for chickens according to this invention will be explained byway of example as follows:

ANTICOCCIDIUM FEED The number of deaths Control 7 Anticoccidium feed Further nitrofuran derivatives of this invention can be employed for preservation of food. In this case such preservation effect may be exhibited by mixing the nitrofuran derivatives with the food to be preserved and dissolving them by heating or dipping the food in a solution of nitrofuran derivatives. The following example explain fully said preservation effect of the nitrofuran derivatives on the foods, sausage and fresh fish;

PRESERVATION EFFECT OF NITROFURAN DERIVATIVES (A) PRESERVATION OF SAUSAGE 30 kg. of meat, 750 gms. of table salt and 120 gms. of niter are fully mixed and kept it in icebox for 12 hrs. The product is divided into three (1), (2), (3).

( 1) No addition of nitrofuran derivatives.

(2) 25 'y/ g. of 5-nitro-2-furyl-u-phenyl acryl amide is added.

(3) /g. of 5-nitro-2-furyl-a-furyl acryl amide is added.

Each of them is charged in a container by means of airstuifer and boiled at 80 C. for 40 minutes. In a thermostat (37 C.) they are measured on their preservation period of time elapsed until evolution of gases from interior resulting from the putrefaction which is shown as follows:

(B) PRESERVATION OF FRESH FISH NH3-N, Weight of Samples mgJlOO g. samples,

gms.

The new nitrofuran derivatives according to the present invention can be used for preservation of all substances apt to be attacked with microorganisms. For example, when S-nitro-Z-furyl-a-phenyI acryl amide or S-DitIO-Z-fUI'Yl-ocfuryl acryl amide is added in a proportion of about 1:300,000 to starch-paste, the preservation period of time is confirmed to extend about 15 days over that of the control.

What is claimed is:

l. A nitrofuran derivative of the formula:

OzN HCH=C-CO R2 wherein R is selected from the group consisting of phenyl radical and furyl radical and R is selected from the group consisting of hydroxy radical and amide and radical. 2. 5-nitro-2-furyl-a-phenyl acrylic acid of the formula:

OaNL J C1i=C-C 0 OH O Q 3. 5-nitro-2-furyl-a-phenyl acryl amide of the formula:

4. 5-nitro-2-furyl-a-furyl acrylic acid of the formula:

5. 5-nitro-2-furyl-a-furyl acryl amide of the formula:

(References on following page) 7 8 References Cited in the file of this patent Maxim et aL: Bull. Soc. Chim. [5], vol. 2, pages 582- Chemical Abstracts: vol. 43, cols. 9333-4 (1949). 591 9 0- 7 Chemical Abstracts, Vol. 44, cols. 5372 to 5373 (1950). Chemlcal Abstracts, (1018- 929 and 3383 Chemical Abstracts, vol. 45, column 6691 (1951). Crawfordct 1 C 1959, Pages 2 Dunlop et al.: The Furans, pages 163 to 165; pages 5 Chemical Abstracts, vol. 53, column 3529 (1959). 619 to 622, ASC Monograph N0. 119, Reinhold Publish- Chemical Abstracts, vol. 53, column 11,699 (1959). ing Corporation, New York, N.Y. (1953). a 7 

1. A NITROFURAN DERIVATUVE OF THE FORMULA: 